CN1036135A - Growth inhibitor and application thereof - Google Patents

Growth inhibitor and application thereof Download PDF

Info

Publication number
CN1036135A
CN1036135A CN89101050A CN89101050A CN1036135A CN 1036135 A CN1036135 A CN 1036135A CN 89101050 A CN89101050 A CN 89101050A CN 89101050 A CN89101050 A CN 89101050A CN 1036135 A CN1036135 A CN 1036135A
Authority
CN
China
Prior art keywords
cyclodextrin
growth
derivant
steroid
compositions
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN89101050A
Other languages
Chinese (zh)
Other versions
CN1038304C (en
Inventor
摩基斯·朱旦·福克迈
波耳·波格·威治
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CN1036135A publication Critical patent/CN1036135A/en
Application granted granted Critical
Publication of CN1038304C publication Critical patent/CN1038304C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Images

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/50—Fibroblast growth factor [FGF]
    • C07K14/503—Fibroblast growth factor [FGF] basic FGF [bFGF]
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/21—Acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/22—Lipids, fatty acids, e.g. prostaglandins, oils, fats, waxes
    • A61L2300/222—Steroids, e.g. corticosteroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/80—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special chemical form
    • A61L2300/802—Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Transplantation (AREA)
  • Biochemistry (AREA)
  • Nanotechnology (AREA)
  • Biophysics (AREA)
  • Ophthalmology & Optometry (AREA)
  • Biomedical Technology (AREA)
  • Dermatology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Biotechnology (AREA)
  • Materials Engineering (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Botany (AREA)
  • Polymers & Plastics (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Genetics & Genomics (AREA)

Abstract

Suppress to comprise the human mammiferous pathologic or the growth of other cell or tissues that do not expect to have by giving a kind of compositions, said composition is specially to be made up of (1) a kind of water-soluble cyclodextrin sulfate and (2) a kind of growth inhibited organic compound.Growth inhibited organic compound (2) can be a kind of inhibiting steroid that just do not have when not having (1), or for a kind of may be organic compound active growth inhibitor, that its effect can be strengthened by (1).The invention provides a kind of inhibition angiogenesis and control tumor growth, and other disease relevant with the cell or tissue that does not the expect to have growth that comprises angiogenesis of treatment and the method for pathological state.

Description

Growth inhibitor and application thereof
The application is the part subsequent application of the 145th, No. 407 application of submission on January 19th, 1988.
The present invention generally relates to and uses a kind of new growth inhibition composite that the pathologic or unwanted growth of mammalian cell or tissue is suppressed.More particularly, the present invention relates to a kind of growth inhibition composite that contains a high dissolubility cyclodextrin derivative and that hide an or active growth inhibited chemical compound, and use said composition to suppress to comprise unwanted or pathologic growth of the angiogenesis relevant with malignant tumor.
The inhibitory action of heparin and angiogenesis
Angiogenesis causes the growth of new blood capillary, and fetal development, corpus luteum are formed and normal processes such as wound healing is important, and it also is that the important component part with pathological process such as tumor generation is promised in chronic inflammatory disease, some immunity.Generally believe that at present most of malignant tumor cause angiogenesis, and angiogenesis is indispensable to the continued growth of malignant tumor and survival.Angiogenesis is the glycosuria retinitis, the key component of many pathology of eye such as fibrous tissue formation and neovascular glaucoma behind the crystal.In addition, think that at present angiogenesis also is other non-tumor generative nature pathological conditions, as rheumatic arthritis (unusual blood capillary growth can destroy articular cartilage), (the unusual blood capillary that neonate occurs generates hemangioma, sustainable more than 2 years), fibrohemangioma (producing), and the key component (seeing Folkman and Klagsbrun, Science235:442(1987)) of psoriasis (hyperplasia and come off be decided by the growth of unusual blood capillary in the corium) at nasopharynx part.
Found heparin (or heparin fragment) in the past but and cortisone synergism inhibition angiogenesis.This Application No. of submitting on August 16th, 1984 is to address in 641,305 the application, and its content is listed this paper list of references in.When they are together suffered from the mouse of some tumor, can suppress to support tumor growth basic blood capillary generation and destroy the blood supply of supporting tumor growth.(" blood vessel is how to regulate normal and neoplasia tissue? " (G.H.A.Clowts Memorial Award Lecture), Judah Fdkman, Cancer Research, 46:467(1986)) the historical and relevant subject content of this discovery summarized in a literary composition, and the content of this article technology volume as a setting is the application's list of references.
Cortisone is a kind of anti-inflammatory agent, itself can not suppress the blood capillary growth.According to people such as Shubik (J.Nat ' l Cancer Inst.57:769, (1976)) report, 6 Alpha-Methyl prednisolones can partly suppress the angiogenesis of Mus cheek pouch tumor under certain condition, but tumor growth does not stop.Even other many article reports have a large amount of cortisones to exist, tumor is continued growth still.Also have and report that methoxyl group Progesterone, dexamethasone and cortisone still less can suppress the angiogenesis of rabbit corneal tumor, estradiol and testosterone then invalid (Gross et al., Proc.Nat ' l.Acad.Sci.USA 78:176(1981)).
Known now that except cortisone some other steroid and heparin or heparin fragment use also together can successfully suppress angiogenesis.These have the steroid of effect to be called " heparin dependency steroid ", because the effect of heparin is exclusive (being to think so so far).The discovery of these angiogenesis inhibition steroid and characteristic are at " a class new steroid that suppresses angiogenesis in the presence of heparin or heparin fragment " (R.Grum, S.Szabo and J.Folkman, Science 230:1375(1985)) with " becoming angiogenesis inhibition steroid " (J.Folkman and D.E.Ingber, Annals of Surgery, discuss 206:374(1987)), these will classify the application's list of references as with background technology.
Heparin-kind of mucopolysaccharide-be a kind of composition of many tissues, especially liver and lung and several mammals mastocytes, from chemical terms, heparin be D-glycosamine and D-glucuronic acid with α, the sulphation copolymer that the β glycosidic linkage links to each other.Yet though half a century medically heparin is used as anticoagulant always, the true nature that the definite structure of heparin and its anticoagulant act on is not admittedly verified as yet.The main difficulty of determining heparin structure is the complexity of itself and itself is not material a kind of homogeneous, well-defined.Heparin is that molecular weight is 5,000 to 40,000 polydispersion body.On a specific chain, also have such as structural changes such as sulphation, N-acetylation and uronic acid residue C-5 epimerizations.
The major defect that suppresses angiogenesis with heparin and steroid is that by the heparin that distinct methods and different company produce, although its blood coagulation resisting function is similar, the activity difference of their angiogenesis inhibitor is quite big.Because raw material is different with manufacture method, the accurate component of commodity heparin is also obviously different.Some heparin inhibition angiogenesis that can combine with cortisone, and other heparin does not just have this effect.In fact,, can increase the dosage of some heparin in order to reach this effect, but because the blood coagulation resisting function of heparin, use may give rise to trouble like this.Second shortcoming is, though when proper ratio being arranged when the use suitable dose and with steroid, heparin suppresses corresponding hepatoma growth significantly, even when slightly higher dosage and ratio, can promote tumour regression, but when using high dose level more and to the ratio of steroid when high, heparin also can recover the ramp of tumor.Obviously the positive-negative regulating factor that has angiogenesis in the heparin, this may produce trouble when suitable administration.The anticoagulant active of heparin can bring another shortcoming, is to avoid hemorrhage, must be limited in during administration than low dosage level or employing oral administration.At last because heparin can not see through cornea, institute think that corneal produces blood vessel formation against function and can not be outside cornea local application.
Cyclodextrin
Cyclodextrin (following represent its DANFU number with CD or CDs respectively for simplicity) is for containing the member cyclic oligosaccharides of 6 glucofuranose units at least.Although known CDs with 12 glucofuranose units, just first three homologue of having been studied widely.These chemical compounds have the chemical constitution that simply, clearly limits shown in Fig. 1 (A).Lower molecular weight α in whole description, β and r-CDS use common name, and the chemical constitution referring to shown in Fig. 1 (A) wherein is respectively n=6, and 7, or 8 glucofuranose units.CDS at first finds as the degradation product of starch about the beginning of this century, and the Schardinger proof can make these chemical compounds with soaking numb bacillus cereus (Bacillus Macerans) diastatic action in starch.In older document, these chemical compounds often are called the Schardinger dextrin.They also are called loop chain starch sometimes.
On the topology, CDS can be represented as an annular surface body shown in Fig. 1 (B), it top mainly by-CH 2The OH group is arranged in wire, and bottom is accessory hydroxyl group.The channel open test pit coaxial with the annular surface body, α-, β-and the diameter in the hole of α-CDS be respectively 5,6, or 7A.U.These caves make cyclodextrin can form the inclusion compound of the external hydrophobic molecule with suitable diameter.
Prepared and described a large amount of CD derivants in the literature.Generally speaking, the CDs of these chemical modifications is by the reaction of uncle who links to each other with carbon 2,3 or 6 or parahydrogen oxygen kan gene, does not obtain and do not destroy α (1 → 4) hemiacetal linkage." No. 147, tetrahedron report; synthesizing of the cyclodextrin of chemical modification " (A.P.Croft and R.A.Bartsch, Tetrahedron39(9): 1417-1474(1983) summarized this based article), this article is classified the list of references (hereinafter referred to as " No. 147, tetrahedron report ") of this paper as.
The table 26(1456 page or leaf of tetrahedron report No. 147 (ibid)) in especially with α-, β-and r-CD sulfate (Na salt) as chemical compound 207,208 with provide for No. 209.The preparation of cyclodextrin sulfate has been described in No. 2,923,704, the United States Patent (USP) of Berger.People's such as Berstein US4,020,160 and people's such as Lewis US4,247,535 and 4,258, No. 180 patent disclosures the use of the cyclodextrin sulfate modified as complement inhibitor.The US4 of Lipari has described a kind of water solublity inclusion compound of steroid and the preparation of modifying beta-schardinger dextrin-in 383,992.The US4 of Pitha discloses gonadal hormone (especially testosterone Progesterone and estradiol) and hydroxyl butyl-β-CD or poly--β-CD in 596,795 with the method for their inclusion compound form administration (through the Sublingual or anus approach).Aforementioned documents is all less than showing or clear and definite summary of the invention as this paper description and claim.
We have been found that at present, when some simple and very soluble in water cyclodextrin derivative uses with potential growth inhibited sex steroid such as cortisone or hydrocortisone or on-steroidal growth inhibited organic compound, can suppress angiogenesis effectively and do not show the character that does not expect to have of heparin.
One of purpose of the present invention provides a kind of new compositions that contains a cyclodextrin derivative and a growth inhibition chemical compound, and said composition can suppress cell or tissue growth, the especially angiogenesis of mammals (comprising the mankind) effectively, or the treatment tumor.
Another object of the present invention provides the pharmaceutical preparation that contains a kind of highly-water-soluble cyclodextrin derivative, especially cyclodextrin sulfate and one or more sterids.
Another object of the present invention provides a kind of by suppressing that unwanted angiogenesis is treated the relevant with angiogenesis of mammal (comprising the mankind) or being the disease of feature or the method for state with the angiogenesis.
Further purpose of the present invention provides a kind of treatment and suffers from the mammal of tumor (comprising the mankind) with the method that suppresses and/or the regressing tumors piece is grown.
Those skilled in the art are by reading the following description and the claim that awaits the reply, will clear and definite these and other purposes of the present invention, aspect and advantage.
The invention provides the compositions that do not expect or pathologic cell or tissue growth of a kind of inhibition mammal (comprising the mankind), described compositions comprise mainly by (1) a kind of be highly susceptible to water-soluble α-, β-, or r-cyclodextrin derivative and (2) a kind of potential growth inhibited sex steroid or a kind of on-steroidal growth inhibited organic compound activating agent that combines and form.
The present invention further provides the method that do not expect or pathologic cell or tissue growth (comprising angiogenesis) of a kind of inhibition mammal (comprising the mankind), this method comprise give mainly by (1) one highly-water-soluble α-, β-or the active agent of r-cyclodextrin derivative and (2) one potential growth inhibited sex steroids or the organic growth inhibited amount of an on-steroidal growth inhibited.Method of the present invention is by mixing two kinds of active agents and by single approach administering drug combinations, perhaps using each active agent respectively and make it in vivo in conjunction with finishing.According to alternative way, two kinds of active agents can need only both combinations promptly in vivo respectively by with identical or different administration.
The present invention further provides a kind of method of inhibition mammal (comprising the mankind) angiogenesis, this method comprise give mainly by (1) one highly-water-soluble α-, β-or r-cyclodextrin derivative and (2) are at least a is selected from the angiogenesis amount of suppression compositions of activating agent that potential growth suppresses the angiogenesis inhibitor composition of steroid and on-steroidal growth inhibited organic compound, and described derivant is characterised in that when its dissolubility is 0 ℃ the solvable at least 20mg of terminating an agreement in every 100ml water.
The present invention further provides the method for the smooth muscle cell pathologic growth of a kind of inhibition (need treat) mammal (comprising the mankind), this method comprises and containing with the compositions of highly-water-soluble cyclodextrin derivative as the growth inhibited amount of activating agent, wherein preferred highly-water-soluble cyclodextrin sulfate for be basically by α-, β-or the r-cyclodextrin on sulfate anion and physiologically acceptable avirulence cation be combined into.
With reference to following detailed, preferential embodiment and accompanying drawing can more fully be understood the present invention:
Fig. 1 (A and B) be (A) α-, β-and r-cyclodextrin chemical constitution and (B) diagram of the 3D shape of these cyclodextrin describe.
(β-CD-TDS) or heparin are to (A) rat aorta smooth muscle cell and (B) influence of bovine aortic smooth muscle cells growth for Fig. 2 (A and B) graphic extension beta-schardinger dextrin-four sulfate.
External reagent (A) shows only with endotoxin (being matched group) the photo of the influence of the blood capillary generation of endotaxin induction Fig. 3 (A-D) on the rabbit corneal in order to be presented at; (B) show only with hydrocortisone (second group); (C) show with β-CD-TDS+ hydrocortisone (the 3rd group); (D) show only with β-CD-TDS.Experimental detail is referring to text.
The influence that the polymer that is mixed with different reagent that Fig. 4 graphic extension implant to continue discharges prolongs blood capillary due to the endotoxin in the rabbit corneal.(0)=only with endotoxin (matched group); (0)=β-CD-TDS+11-deoxidation skin alcohol (second group); (△)=only usefulness cortexolone (the 3rd group) and (0)=only with the 4th group of β-CD-TDS().Experimental detail is referring to text.
The inventor has sought the chemical compound beyond a kind of non-heparin, this chemical compound does not have the shortcoming of heparin, but when it combines with a steroid, can suppress cell or tissue growth that do not expect or pathologic (comprising angiogenesis) effectively, so it especially comprises that to control or elimination human mammiferous tumor is effective.
(comprise β-CD) can form the water solublity inclusion compound, because known cyclodextrin so we attempt to use the CDs of unmodified and the mixture of hydrocortisone with steroid.Yet, find this effect (shown in embodiment 18-20 (hereinafter the 7th joint)) that thing And does not suppress angiogenesis of closing that mixes.
Surprisingly, we find to encircle the highly-water-soluble salt of mush and can suppress angiogenesis effectively with combining as steroid such as hydrocortisone.Especially β-CD four sulfate (best results of β-CD-TDS).In other words, the compositions of steroid and water soluble cyclodextrin derivant comprises that to suppressing mammiferous the treatment of the cell or tissue of the not expecting growth of angiogenesis is effective.
It is recursive that the effect of having found CD sulfate that this paper is discussed and other highly-water-soluble derivant is done detection at chicken CAM (CAM).This detection method has been used as the standard method (Klagsbrun et al, Cancer Res.36:10(1976) of the angiogenesis vigor that detects different material).Three batches by embodiment 1(A) β-CD-TDS of described method preparation compares with the CAM detection method.Highly-water-soluble CD derivant all has the advantage of the angiogenesis inhibitor of heparin, and does not have the shortcoming of heparin.These find also to have overcome when combining with the inhibition angiogenesis with suitable steroid, and the heparin role is unique this technology prejudice.
We find that also highly-water-soluble CD derivant such as β-CD-TDS can not use with the non-steroidal compound (itself just has the chemical compound of certain anti-angiogenesis activity) that suppresses growth when having the external source heparin to exist, its performance has surprising potential anti-angiogenesis activity.The example of these non-steroidal compounds comprises but is not only limited to, as L-2-azetidine carboxylic acid (embodiment 24 sees below), along hydroxyproline or 3, proline analogs such as 4-two hydroxyprolines and trans retinoic acid.L-2-azetidine carboxylic acid
In the article of Merch, address the description that is listed as the relevant on-steroidal growth inhibited chemical compound as proline analogs of this paper list of references (seeing Ingber and Folkman Lab Investng 59:44(1988) as chemical compound 911).
In order clearly steroid (do not have the external source heparin to exist, do not have inherent anti-angiogenesis activity) to be distinguished with on-steroidal growth inhibited chemical compound, use " potential growth inhibitor " this limited term here.This paper said " non-steroid " is meant that this chemical compound does not have the carbocyclic ring architectural feature of sterin.
The soluble derivative of cyclodextrin
According to the present invention, the highly-water-soluble CD derivant that has nonionic or ion substituent is useful to the growth that suppresses not expect.Suitable highly-water-soluble CD derivant comprises and has but be not limited to the substituent α of nonionic such as methyl, ethyl, β and r-CD derivant, and simultaneously in order to increase the hydrophilic of CD, the many oh groups on these derivants are replaced by other group.These groups can comprise ester, ether, thioesters, thioether, carbonic acid or other group by polarity or hydrogen bond composition change hydrophilic active, or they can comprise that permission participates in keeping oh group to obtain the part of hydroxyl replacement of better hydrogen bond.
Useful in the present invention CD derivant all is a high-hydrophilic, so very soluble in water.Need not theoretical the support, we believe that high water-wet behavior is very important for making it to interact with cell surface.We think external source steroid provided by the invention and the inherent complex capabilities synergism of CD structure equally to suppress angiogenesis effectively, and the highly-water-soluble of derivant is a key factor.We think, can determine to represent hydrophilic active roughly with the affinity of water by measuring water solublity.It is important measuring under 0 ℃ uniform temp, because under higher temperature, most of suitable derivant has very high dissolubility and makes significant mensuration be difficult to carry out.
As show shown in the II (embodiment 18-22, hereinafter the 7th joint), most of soluble derivative (0 ℃ of mensuration) demonstrates the highest anti-angiogenesis activity.The β-CDYan Shengwu of CDs is seemingly the most effective.In general, record in 0 ℃ that dissolubility is at least about 15mg/100ml in distilled water, be preferably, preferably be about 30mg/100ml person and be suitable at least about 20mg/100ml.Here all dissolubility all refer to the dissolubility of substantially anhydrous relatively derivant, these derivants are the salt time-like, then are the anhydrous sodium salt form.Term " very easily molten " is meant that here measuring its dissolubility as stated above is at least 15mg/100ml person.
Having the substituent highly-water-soluble CD of ion or nonionic derivant may be in the existing good characteristic of some example invading the exterior, and these derivants also belong in the present invention's scope.Although generally speaking high water reactive derivative all is useful, preferably salt derivative.
Term used herein " salt derivative " is meant the ionic compound that is obtained by CD and suitable agent reaction.Preferred salt derivative is by a substituent cyclodextrin with the sulfate of being selected from, phosphate, carboxylate or its mixture and an atoxic physiologically acceptable anion be combined into.Many described preferred derivants are known compound (see No. 147, tetrahedron report, ibid).But many potential useful forms all be known compound structurally or variant chemically.They also have several different substituent groups, and as the cyclodextrin propoxyl group sulfate among the routine 1D, we think and did not report as yet before this.The preferred salt form of some of derivant is sodium and potassium salt, because they tend to increase the dissolubility of water to organic anion.Said useful salt derivative shows the electrolytic conduction and the Penetration Signature of electrolyte and polyelectrolyte in aqueous solution.Particularly preferred salt derivative is beta-schardinger dextrin-four sulfate (β-CD-TDS).
The α that in claim of the present invention, mentions-, β-and the r-CD Sulfates all be useful.Wherein β-CD sulfate preferably can adopt each glucose unit that the product of different degree is arranged, and as per two glucose units a sulfate groups is arranged on average, or each glucose unit has two sulfate groups.Wherein preferably every glucose unit has the cyclodextrin of two sulfate groups, and especially preferred is β-CD-TDS, and its average each glucose unit has two sulfate groups.
Steroid and on-steroidal organic compound
Effective and the available steroid that the present invention relates to has:
17 α, 21-dihydroxy-4-pregnene-3,11,20-triketone and 21-acetas (or cortisone) thereof;
11-α, 17, the 21-trihydroxy is pregnant-4-alkene-3,20-diketone (or 11 α hydrocortisone);
11-β, 17 α, the 21-trihydroxy is pregnant-4-alkene-3,20-diketone (or hydrocortisone);
17 α, the 21-dihydroxy is pregnant-4,9(11)-and diene-3, the 20-diketone; 15 α, 17 α, 21-trihydroxy 4-pregnene-3,20-diketone;
16 α, 17 α, 21-trihydroxy-6 Alpha-Methyl is pregnant-4-alkene-3, the acetal of 20-diketone-21-acetas-16,17 acetone;
6 α-fluoro-17 α, 21-dihydroxy-16 Beta-methyl-pregnant 4,9(11)-and diene-3, the 20-diketone;
6 α-fluoro-18 α, 21-dihydroxy-16 Beta-methyl-pregnant-4,9(11)-and diene-3,20-diketone-17,21-diacetate esters;
6 β, 17 α, the 21-trihydroxy is pregnant-4-alkene-3, the 20-diketone;
17 α, the 21-dihydroxy is pregnant-4-alkene-3,20-diketone-21-acetas;
17 α, the 21-dihydroxy is pregnant-4-alkene-3,20-diketone (or cortexolone);
9 β, 11 beta epoxides-17 α, 21-dihydroxy-2 Alpha-Methyl is pregnant-4-alkene-3,20-diketone-21-acetas;
17 α, 21-dihydroxy-11 Alpha-Methyl is pregnant-4-alkene-3, the 20-diketone;
9 α, 11 β-two chloro-, 17 α, the 21-dihydroxy is pregnant-4-alkene-3,20-diketone-21-acetas;
17 α, 21-dihydroxy-6 α, 16 alpha, alpha-dimethyls are pregnant-4-alkene-3,20-diketone-21-acetas;
17 α, 21-dihydroxy-16 Alpha-Methyl is pregnant-4,9(11)-and diene-3,20-diketone-21-acetas;
17 α, 21-dihydroxy-16 Beta-methyl is pregnant-4,9(11)-and diene-3,20-diketone-21-benzoate;
6 α-fluoro-17 α, 21-dihydroxy-16 Beta-methyl is pregnant-4,9(11)-and diene-3,20-acetas-21-benzoate;
17 α, 21-dihydroxy-16 Beta-methyl is pregnant-1,4,9(11)-and triolefin-3,20-diketone-17 sodium succinate monohydrate;
9 α-fluoro-11 β, 16 α, 17 α, the 21-tetrahydroxy is pregnant-4-alkene-3,20-diketone-16,21-diacetate esters;
17 α; 21-dihydroxy-16 Alpha-Methyl is pregnant-1,4,9(11)-triolefin-3,20-diketone-21-sodium succinate monohydrate;
6 α-fluoro-17 α, 21-dihydroxy-16 Beta-methyl-pregnant-1,4,9(11)-and triolefin-3,20-diketone-21-sodium succinate;
Deoxycorticosterone;
Testosterone;
Estrone; With
Tetrahydrochysene S.
The steroid that does not more preferably have glucocorticoid and mineralocorticoid activity, because this activity is the effect that does not expect to have, it has limited the scope of application and the dosage that reaches the object of the invention.Wherein more preferred steroid is 11 α, 17, the 21-trihydroxy is pregnant-4-alkene-3,20-diketone (or 11 α-hydrocortisone), 17 α, the 21-dihydroxy is pregnant-4-alkene-3, and 20-diketone (Compd S 11-deoxycortisol or 11 deoxidation skin alcohol) and 17 α, 21-dihydroxy pregnant-4,9(11)-and diene-3, the 20-diketone.
When the water soluble cyclodextrin derivant that not the present invention relates to existed, steroid itself just can not suppress angiogenesis effectively can not make tumor regression.
As pointed out in the present invention, combine the growth inhibitory activity of having strengthened the on-steroidal organic compound with water soluble cyclodextrin derivant.Comprise L-2-azetidine carboxylic acid effectively and by on-steroidal growth inhibited organic compound of the present invention, along hydroxyproline and 3, proline analogs such as 4-dihydroxy proline and trans retinoic acid.
In addition, detecting proof with following arbitrary bioassay method has any on-steroidal organic compound of growth inhibitory activity to combine in the method that all can be used for claim of the present invention with cyclodextrin derivative.
Existing several biology, method of testing was estimated the growth inhibited ability of a material, and rabbit corneal is the basis of setting up one of these methods.Cornea is avascular, can make a pouch therein, implantable tumour transplatation thing when rabbit is anaesthetized.From host's vascular bed, separate tumor.New blood capillary will can be measured the speed of angiogenic growth soon towards the Chang And of the direction Sheng of tumor.(more detailed description of method referring to Gimbrone et al, J.Nat ' l Cancer Inst.52:413(1973), this article has been listed this paper list of references in).
More economical bioassay method is the CAM that utilizes Embryo Gallus domesticus, for convenience, hereinafter it is abbreviated as " CAM method ".(more detailed description of relevant CAM method is referring to Folkman et al.Science 221:719(1983), this article has been listed the list of references of this paper in).As hereinafter the 7th saving the typical CAM method that is adopted among the embodiment, 16 eggs are used in each experiment.The methylcellulose garden sheet that will contain the 2mm diameter of substances is attached on the CAM of 6 days Embryo Gallus domesticus, cultivates in the humidification incubator that contains 3% carbon dioxide in culture dish, and (8 days Embryo Gallus domesticus) checks film after 2 days under amplification 6-10 stereoscopic microscope doubly.Form avascular area around the sheet of methylcellulose garden and promptly prove the inhibitory action of substances angiogenesis.The avascular area that the avascular area of 4mm is expressed as (++) and 2mm is expressed as (+).2mm and 4mm with on the inhibition ability be to be decided to be the percentage ratio that (++) or (+) person accounts for total ovum number (normally 16) as this test acceptance of the bid, promptly the percent of " success " is represented.0% is illustrated in that this substances does not have inhibitory action under this experimental condition.
By an amount of substances of diffusion in 0.45% methylated cellulose aqueous solution, in the Teflon mould, respectively apply 10ml, about one hour of air drying in the laminar flow fume hood then obtains to continue the methylcellulose garden sheet that discharges.
Very big characteristics of CAM method are that Embryo Gallus domesticus has very high sensitivity to toxicant.The shortage toxicity of a material is associated with shortage toxicity when giving other animals with this material in the CAM method in addition.
Use and using method
Compositions of the present invention comprises that to suppressing the do not expect cell and the tissue growth of angiogenesis are useful, certainly, contain water solublity α-, β-or the present composition of r-CD derivant and steroid can be used for the human mammal that comprises of this treatment of needs.For example, suffer from the mammal that tumor need be treated, available compositions of the present invention is treated.Though incomplete as yet bright Liao it is believed that with present composition treatment and can suppress the necessary new capillary angiogenesis of tumor growth, it is enough for its growth even the essential nutrient supply of surviving that this makes that tumor can not get.Therefore, when treating, comprise that the mankind's mammal tumor can not be grown according to the present invention, even forfeiture viability and death.The tumor that the present composition and method are responded has: reticulosarcoma, Lewis lung tumor, B-16 melanoma and bladder cancer etc.
Handle sophisticated non-growth blood vessel and not influence of vascular tissue with the present composition.Suppress angiogenesis according to the present invention, it except that to the tumor regression of suffering from the tumor animal and shift influential, it is to treating many other diseases also to some extent in order to do suitable.
The present invention further provides that a kind of to treat many be the method for the non-tumor disease of feature with the pathologic cell or the tissue growth that comprise angiogenesis.Therefore the invention provides the method that treatment comprises human mammiferous many non-tumor sexually transmitted disease (STD) reason situation, these diseases comprise rheumatic arthritis (its unusual blood capillary growth can destroy articular cartilage); Hemangioma (abnormal angiogenesis occurs at neonate, and can continue more than 2 years); Blood vessel fiber disease (nose because of in the development); Psoriasis (too much propagation and desquamation may depend on the unusual blood capillary growth in the corium).In addition, the present invention provides Therapeutic Method for many with oculopathy that do not need angiogenesis to interrelate, and fibrous tissue formed and neovascular glaucoma after these oculopathy comprised diabetic retinopathy, crystal.
Method that smooth muscle cell that a kind of inhibition usually occurs grows or the Therapeutic Method of removing the atheromatous plaque of artery-clogging have been the present invention further provides behind mature blood vessel.
An embodiment according to the inventive method mixes active agent before administration, so that steroid or on-steroidal growth inhibited chemical compound and water soluble cyclodextrin derivant administering drug combinations.After making mixture, but its oral administration or gastrointestinal tract are outer by way of administration, as local application, intravenous, intra-arterial or subcutaneous injection and with inject and importing body orifice or the mouth of pipe absorb other by way of administration.
Cortisone and its physiologically acceptable non-toxic derivative (as acetas) and the useful steroid of other the present invention only are slightly soluble in water, yet when they mixed with water soluble cyclodextrin derivant of the present invention, resulting complex had just increased water solubility.Thereby make compositions of the present invention be easier to use.The 11-αYi Gouti of the term that uses in description of the present invention and claims " cortisone " and " hydrocortisone " and hydrocortisone comprises steroid itself and their derivant and structural variant.
According to another embodiment of the inventive method, active agent can be used separately, and make two kinds of active agent combinations in vivo.In this embodiment, two kinds of active agents can as long as in a single day both enter in the body, can form the compound mixture of these two kinds of active agents by identical or different use by way of separately importing in the body.
Because the restriction that cortisone, hydrocortisone or 11 αYi Goutis are subjected in the use is so dosage is limited.Because used here CD derivant does not demonstrate toxicity (as follows) when having the anticoagulation effect and giving following dosage in CAM test yet, so used dosage when using the dosage of steroid can reach at least to share with heparin.Oral dose can be higher, for example is enough to determine effectiveness and suitable dose by example 3 described simple experiments in 641, No. 305 applications of the United States Patent (USP) of submitting on August 16th, 1984, and this paper list of references is listed in this patent application in.
Because specific tumor and needing suppresses or the asynchronism(-nization) of regressing tumors, institute is so that the tumor growth inhibition is also different with the dosage that disappears.The time that tumor size influence during begin treatment is disappeared fully.Because cortisone with or do not use and can cause pulmonary infection after several days with β-CD-TDS(Na), can adopt suitable antibiotic to prevent according to the present invention.This antibiotic can mix as the mixture administration with water soluble Beta-cyclodextrin of the present invention and steroid or on-steroidal growth inhibitor, perhaps, by independent and water soluble Beta-cyclodextrin of the present invention and the growth inhibitor administration simultaneously of identical or different medicine-feeding way with this antibiotic.
As show shown in the I (hereinafter the 7th joint), as the weight ratio of water solublity CD derivant and steroid greater than 2: 1 or mol ratio greater than 0.4, then can lower anti-angiogenesis activity.The mol ratio of preferred molar range and CD derivant and blood vessel arrestant (steroid or on-steroidal) is 0.004 to 0.7, is preferably 0.04 to 0.7.Back one scope is especially suitable to the external that comprises the collyrium for the treatment of oculopathy.The amount of angiogenesis inhibitor is generally 0.1 to 10mg/ml when mixing with the CD derivant, yet absolute magnitude is decided by administering mode and frequency.
Compositions useful of the present invention preferably uses with suitable carrier, and this carrier is necessary for avirulence and physiologically acceptable, as water or normal saline.Can use dried or in suitable carrier, contain compositions active agent intermixture or that only contain activating agent.
Embodiment
The following examples are used for illustrating the present invention, and still, they not delimit the scope of the invention, and scope of the present invention is by the whole description and the claim decision of awaiting the reply.Outside the person, all amount and ratios all are by weight unless stated otherwise, but for the CAM method, % represents the ratio (seeing above 6.3) of " success ".
Example 1(A-D)
This embodiment illustrated as far as our knowledge goes preparation and the best method of purity ring dextrin sulfate, itself does not belong to content of the present invention this method.
（A）β-CD-TDS（Na）：
Beta-schardinger dextrin-(99% pure two hydrates) is available from Chemalog company (branch company of General Dynamics company, South Plainfield, New Jersey).
(4.4mmol, promptly about 92meq-OH) is dissolved in the 250ml dimethyl formamide (DMF) with the 5.0g beta-schardinger dextrin-, once is added on 15.0g(CH in this solution 3) 3N-SO 3(108mmol), reactant mixture is heated to 70 ℃.After 2 hours, be settled out a kind of jelly.Mixture remains in 70 ℃ of thermal agitations, is cooled to room temperature then.Pour out and discard the DMF layer, solid residue is dissolved in the 250ml water, and then add the sodium acetate of 75ml30%, with this mixture thermal agitation 4 hours, add in the 4000ml ethanol again, static spending the night filtered and obtained crystalline solid.Filter cake is washed with reuse diethyl ether behind the absolute ethanol washing earlier.And then with product at P 2O 5Middle vacuum drying obtains the 10.3g white powder.Product is moisture absorption.
Assay products under the condition of water absorption minimum, results of elemental analyses is as follows: C=18.84, H=2.65, S=17.33(calculates C 6H 8O 11S 2Na 2: C=19.67, H=2.19, S=17.49).(α) 22 D=75 ° (C=2.63 in 0.5MNacl).Analyze that on average to have two hydroxyls to be substituted consistent with each glucofuranose unit of envisioning, promptly each CD molecule has 14 hydroxyls to be substituted.The productive rate that this β-CD-TDS salt calculates is 10.96 grams, Duos 6% approximately than the 10.3g that records.
(B) α-and r-CD-SCNa salt
Use 86mmol CH during except preparation α-CD 3N-SO 3, be outside the 117mmol during preparation r-CD, other steps are all the same with said method.
Sulphation α-CD salt is analyzed result: C=18.76; H=2.60; S=16.22, this on average has 11.7 hydroxyl units to be substituted with each α-CD molecule to conform to approximately.
Sulphation r-CD salt is analyzed result: C=18.96; H=2.69; S=14.84.This on average has 14 hydroxyl units to be substituted with each r-CD molecule to conform to approximately.
(C) β CD-SO 4(Na salt) (7.1 weight %S):
The 1.0mg beta-schardinger dextrin-is dissolved among the 50ml DMF, adds 883mg(CH 3) 3NSO 3(7.2 equivalent), this solution does not during this period of time precipitate in 75 ℃ of maintenances 12 hours.Reactant mixture is cooled to room temperature, in this solution, adds 200ml ethanol again, again the colloidal solution that obtains is added in the 600ml diethyl ether, form white solid after two hours.The solid collected by filtration thing is dissolved in the 30ml water again, solution stirring 2 hours.Pour 900ml2 after the stirring into: 1 EtoH-Et 2In the O solution.Form crystallization after 8 hours, collect this crystallization, use Et 2The O flushing.With product at P 2O 5Last vacuum drying obtains 1.18gm powder (productive rate 72.4%).
Product results of elemental analyses C=32.49; H=4.99; And S=7.06.Show that each β-CD molecule on average has 3.5 hydroxyls to be substituted approximately.
(D) β-CD-propoxylate-14SO 4
From American Mnige-Prodacts company (Hammond 1N) obtains β-CD-(hydroxyl-n-propyl ether), preparation β-CD-(～4Pr～14SO 4) sulfate method as mentioned above.
Example 2-15
Evaluate with the CAM method and among these embodiment hydrocortisone and various dose to be suppressed ability by the angiogenesis that the β-CD-TDS of embodiment 1 method preparation is used in combination generation.All methylcellulose garden sheets all contain 60 μ g steroid, but β-CD-TDS amount is that 100 μ g to 0.05 μ g do not wait.The results are summarized in the table I.From data as can be seen, the CD chemical compound has the inhibition angiogenesis function when suitable low dosage (0.05 μ g), does not show the angiogenesis activation when 2,000 times of concentration nearly.
The table I
The CAM method
Embodiment sequence number hydrocortisone β-CD-TOS (++) (+)
μg μ % %
2 60 100 - 57
3 60 50 60 100
4 60 50 22 55
5 60 25 10 60
6 60 25 18 55
7 60 10 40 70
8 60 10 6 40
9 60 5 0 50
10 60 1 0 50
11 60 1 0 42
12 60 0.5 0 40
13 60 0.1 0 45
14 60 0.1 0 37
15 60 0.05 0 20
Opposite with these results, with 100 μ g α-, β or r-cyclodextrin and 50 μ g CAM that hydrocortisone is done test shows, they all do not have angiogenesis suppression action (on 1mm zone (+) or 2mm zone (++) level all not successfully).
Example 16-17
As show shown in the II, the low but useful activity that is provided by sulphation α-CD and r-CD has been provided example 16 and 17.Embodiment 5 and 6 data are also listed in this table and are compared.
All tests all are to do with 25 μ g indicated CD sulfate and 50 μ g cortisones.
The table II
Embodiment sequence number CD sulfur CAM method
Weight % (+) (++)
% %
16 α 16.2 8 0
17 r 18.9 15 0
5 β-CD-TDS 17.3 60 15
6 β-CD-TDS 17.3 55 18
Example 18-22
This group experiment shows angiogenesis inhibiting activity except the characteristic composite reactive that needs the CD structure, also needs highly-water-soluble.It is to use 50 μ g to the 60 μ g hydrocortisone that are contained in 10 μ l, 0.45% methylated cellulose aqueous solution to do that the CAM method detects.
In order to compare highly-water-soluble CD sulfate, the dissolubility that at room temperature records is too high to be unpractiaca, so all solubility tests should be carried out in 0 ℃ of aqueous water.About water combines with the orderly of itself, can draw one as the metric figure of hydrophobic combination with the water competition.These comparative results are shown in the table III.
Example 18,19 and 20 has been described unsubstituted CDS and shown the result who does not have angiogenesis inhibiting activity in the CAM detection method.Example 21 shows with the result who derives from American Maize-Products company (Hommond, propoxylation β IN)-CD(hydroxyl-n-propyl ether) (every CD molecule on average has 4 hydroxypropyl groups approximately) testing.Example 22 demonstration use-case 1(C) result of the less Sulfated β-CD product testing that obtains.In order intactly to compare the embodiment 16,17 of water solubility and 5 result when also comprising 0 ℃ in the test.
Figure 891010505_IMG2
Example 23
Present embodiment has illustrated that cortexolone and β-CD-TDS are effective especially angiogenesis inhibitor compositionss.Cortexolone is chemically close with cortisone, yet it does not almost have the function of cortisone except having heparin to exist to have under the situation the blood vessel formation against function.
Single with 50 μ g/10 μ l11-deoxidation skin alcohol, show that in the CAM detection method avascular area is 0%.
Share with same dose and 25 μ g/10 μ l β-CD-TDS, show 85% avascular area territory in the CAM detection method, wherein 31% is (++) or higher.
Example 24
Present embodiment has proved the anti-angiogene activity of L-2-azepine butane carboxylic acid, some inherent anti-angiogene activity of this chemical compound itself, and having in the presence of the CD-TDS, its vigor improves greatly, provides routine 24(a at table respectively in the IV) and 24(b) have or do not have CD-TDS and have the result that CAM detects under the situation.
Table IV: L-2-azepine butane
μ g/10 μ l μ gCD-TDS % avascular area
A L-2-azepine butane 400 0 28
B L-2-azepine butane 400 25 100 *
*5% avascular area is 2+, 25% be 3+, promptly have maximum avascular area, greater than 10mm.
Example 25
When the present embodiment proof is used the growth of β-CD-TDS and effects of heparin smooth muscle cell (SMC) separately (when not having external cortisone steroid or other adminiclies), the former effect is about three times of the latter, this active biological detection is to use the tissue culture of rat or bovine aortic SMC to carry out, and dosage range is 0.03 μ g/ml to 400 μ g/ml.
The result is as Fig. 2 (A) with (B).
Example 26
Present embodiment proof β-CD-TDS is used in combination the neovascularization that can suppress cornea effectively with hydrocortisone.
Perlin (Fed.Proc.36:101(1977)) improving one's methods of the rabbit corneal test of describing is as described below, and it is used to detect β-CD-TDS and the bonded effect of hydrocortisone.In this corneal test, the lasting release polymer that at first will be soaked with bacterial endotoxin is implanted in the rabbit corneal.Angiogenesis is similar to observed neovascularization among the patient who does corneal transplantation at refusal in the cornea of the endotaxin induction of slow release from graft.The substances of this experiment is not to import by the second common graft, but drips in the cornea local surfaces with the formation of collyrium.The animal that acceptance is had endotoxic graft is divided into four groups, carries out part (collyrium) treatment: first group, do not treat, in contrast; Second group, only with hydrocortisone (0.5mg/ml); The 3rd group, hydrocortisone-21-phosphate and β-CD-TDS(are respectively 0.5mg/ml and 1.0mg/ml); The 4th group, β-CD-TDS(1.0mg/ml).Fig. 3 (A-D) shows transplanting and treats back 9 days typical consequence.
Shown in the photo of Fig. 3, when hydrocortisone and β-CD-TDS are mixed for cornea to suppressing angiogenesis very effectively (Fig. 3 C).When the result compared with not treatment group or matched group (Fig. 3 C and Fig. 3 A), the effect of this treatment was especially obvious.In fact, treat animal with hydrocortisone and β-CD-TDS, not only the blood capillary growth is suppressed, and established new blood capillary presents disappear (Fig. 3 C) before treatment.On the other hand, use hydrocortisone that angiogenesis is had faint inhibitory action (Fig. 3 B) separately.Single effect (Fig. 3 D) that then produces the minimal irritation angiogenesis with β-CD-TDS.
In other a series of experiments, with people such as Gimbrone (J.Natl Cancer Inst.52:413(1974)) rabbit corneal described tests the anti-angiogenesis activity of estimating that water soluble cyclodextrin derivant and cortexolone combine.In these experiments, make colibacillus endotoxin (17 μ g/mm 3) mix the lasting release polymer (ELvax, Signa Chemical, St.Louis, Mo(hereinafter referred " Elvax ") of polyvinyl acetic acid vinyl ester copolymers) in, its blood vessel that is implanted in rabbit corneal is distinguished between the edge.Use these substances by second Elvax graft that has mixed the special test material.
To contain endotoxic Elvax graft implants in the cornea of 12 rabbits.Animal is divided into four groups then, treats as follows four eyes of each treated animal:
First group, do not treat, in contrast group; Second group, contain 15 μ g/mm 3The Elvax of β-CD-TDS; The 3rd group, with containing 30 μ g/mm 3The Elvax of cortexolone; With the 4th group, final concentration is 15 μ g/mm 3β-CD-TDS and 30 μ g/mm 3The Elvax of the β-CD-TDS of cortexolone and cortexolone mixture.Measuring once the length of new capillary angiogenic growth in per two days with 10 times of slit view volume mirrors (proofreaies and correct extremely ± 0.1mm) with the eyepiece sash.
Only measure length of vessel and then underestimated the degree of anti-angiogenesis activity, because this mensuration can not be estimated the density of blood capillary., vessel density is also evaluated, utilize following standard to come classification: 0=does not have blood vessel/cornea for this reason; 1=1～4 blood vessel/cornea; 2=5～20 blood vessel/cornea; 3=20～50 blood vessel/cornea; And 4=is more than 50 blood vessel/corneas.The meansigma methods that this rank be multiply by the blood vessel greatest length promptly obtains the sxemiquantitative estimated value (length dnesity index) of each cornea vessel density.The result is shown in Fig. 4 and Biao V.
Fig. 4 shows, can be observed the maximum difference of treatment group and matched group angle cornea after implanting the Elvax ball in 13 days.Be shown in the table V in the 13rd day observed blood vessel average length and density.
The table V
The inhibitory action that the corneal medium vessels generates
Inhibitory action (accounting for the percentage rate of untreated matched group)
β-CD-TDS cortexolone β-CD-TDS a
Cortexolone (single using) (single using)
Length of vessel 18% 49% 164%
Vessel density 8% 61% 303%
A. percentage ratio has stimulation greater than 100% expression to angiogenic growth
As show shown in the V, β-CD-TDS and cortexolone suppress the linear growth of blood capillary, are about not treat 18% in the eye.When estimating capillary density, said composition inhibition vessel density is about does not treat 8% in the eye.Otherwise, shown in the table V, use cortexolone to suppress the blood vessel simple interest separately, and vessel density is untreated 61% only for untreated 49%.Unexpected is, the table V shows further that also independent use β-CD-TDS can stimulate angiogenic growth, and length of vessel is about 164% of not treatment group, and density is about 303% of not treatment group.
According to these results, obviously be a kind of effective ways that suppress ocular tissue's angiogenesis with cyclodextrin salt derivative of the present invention and steroid administering drug combinations.

Claims (19)

1, a kind of inhibition comprises the human mammiferous compositions that do not expect or pathologic cell or tissue growth that comprises angiogenesis, it is characterized in that other contain (1) α-, β-or the derivant of r-cyclodextrin and (2) potential growth inhibited sex steroid or on-steroidal growth inhibited organic compound, derivant wherein be during with 0 ℃ dissolubility in distilled water to be at least 20mg/ml be feature.
2, according to the compositions of claim 1, it is characterized in that wherein α-, β-or the derivant of r-cyclodextrin be its anion salt derivant, described derivant has and is selected from the substituent group that sulfate radical, phosphate radical, carbonate and composition thereof person and physiologically acceptable cation are combined into.
3, according to the compositions of claim 2, it is characterized in that wherein α-, β-or the r-cyclodextrin derivative be cyclodextrin sulfate.
4,, it is characterized in that cyclodextrin sulfate wherein is beta-schardinger dextrin-four sulfate according to the compositions of claim 3.
5, according to the compositions of claim 1; it is characterized in that steroid wherein has 17 α and 21 oh groups; 3-and 20-ketone groups, and hydrogen, hydroxyl or methyl group and their avirulence, physiologically acceptable carboxylate, acetylate, acetal and phosphate are arranged at 16.
6, according to the compositions of claim 3; it is characterized in that wherein steroid has 17 α-and 21-oh group; 3-and 20-ketone groups, and hydrogen, hydroxyl or methyl group and their avirulence, physiologically acceptable carboxylate, acetylate, acetal and phosphate are arranged at 16.
7, according to the compositions of claim 4; it is characterized in that wherein steroid has 17 α-and 21-oh group; 3-and 20-ketone groups, and 16 have hydrogen, hydroxyl or methyl group and their avirulence, physiologically acceptable carboxylate, acetylate, acetal and phosphate.
8,, it is characterized in that steroid wherein is cortisone, hydrocortisone or cortexolone according to the compositions of claim 7.
9,, it is characterized in that on-steroidal growth inhibited organic compound wherein is a L-2-azepine butane carboxylic acid, and cyclodextrin derivative wherein is a cyclodextrin sulfate according to the compositions of claim 1.
10, a kind of inhibition comprises the mammiferous method that do not expect to have or pathologic cell or tissue growth that comprises angiogenesis of human body, it is characterized in that giving mammal use a kind of by (1) α-, β-or r-cyclodextrin derivative and (2) potential growth inhibited sex steroid or on-steroidal growth inhibited organic compound be the compositions of the growth inhibited amount of main active ingredient, derivant wherein is that to be no less than 20mg/100ml water with its dissolubility in distilled water in 0 ℃ the time be feature.
11, a kind of inhibition comprises the method for human mammiferous angiogenesis, it is characterized in that giving mammal use a kind of by (1) α-, β-or r-cyclodextrin derivative and (2) potential growth inhibited sex steroid or on-steroidal growth inhibited organic compound be the active agent of the growth inhibited amount of Main Ingredients and Appearance, derivant wherein with its 0 ℃ in distilled water dissolubility to be no less than 20mg/100ml water be feature.
12, according to the method for claim 10, it is characterized in that wherein α-, β-and the r-cyclodextrin derivative be the salt that the anionic derivative of cyclodextrin constitutes basically, this derivant has and is selected from the substituent group that sulfate radical, phosphate radical, carboxylate radical and composition thereof combine with an avirulence, physiologically acceptable cation.
13, according to the method for claim 12, it is characterized in that wherein α-, β-and r-cyclodextrin salt be cyclodextrin sulfate.
14,, it is characterized in that salt wherein is beta-schardinger dextrin-sulfate according to the method for claim 13.
15, according to the method for claim 10; it is characterized in that wherein steroid has 17 α-and 21-oh group; 3-and 20-ketone groups, and 16 have hydrogen, hydroxyl or methyl group and their avirulence thereof, physiologically acceptable carboxylate, acetylate, acetal and phosphate.
16,, it is characterized in that steroid wherein is meant cortisone, hydrocortisone or cortexolone according to the method for claim 10.
17,, it is characterized in that on-steroidal growth inhibited organic compound wherein is a L-2-azepine butane carboxylic acid according to the method for claim 10.
18, a kind of inhibition comprises the method for human mammal smooth muscle cell pathologic growth, it is characterized in that giving the α that mammal uses growth inhibited dosage-, β-or r-cyclodextrin derivative, this derivant is that to be at least 20mg/100ml water with it at 0 ℃ of dissolubility in distilled water be feature.
19, according to the method for claim 18, it is characterized in that further comprising giving some potential growth inhibited sex steroids or on-steroidal growth inhibited organic compound that derivant wherein is that to be at least 20mg/100ml water with its dissolubility in distilled water 0 ℃ the time be feature.
CN89101050A 1988-01-19 1989-01-17 Growth inhibiting agent and use thereof Expired - Fee Related CN1038304C (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US14540788A 1988-01-19 1988-01-19
US145,407 1988-01-19
US29563889A 1989-01-10 1989-01-10
US295,638 1989-01-10

Publications (2)

Publication Number Publication Date
CN1036135A true CN1036135A (en) 1989-10-11
CN1038304C CN1038304C (en) 1998-05-13

Family

ID=26842946

Family Applications (1)

Application Number Title Priority Date Filing Date
CN89101050A Expired - Fee Related CN1038304C (en) 1988-01-19 1989-01-17 Growth inhibiting agent and use thereof

Country Status (11)

Country Link
EP (1) EP0398925B1 (en)
JP (1) JP2995069B2 (en)
KR (1) KR900700114A (en)
CN (1) CN1038304C (en)
DE (1) DE68910113T2 (en)
DK (1) DK171390A (en)
ES (1) ES2017808A6 (en)
GR (1) GR1000597B (en)
IE (1) IE64346B1 (en)
IL (1) IL88970A (en)
WO (1) WO1989006536A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101946008A (en) * 2007-12-12 2011-01-12 鹿特丹伊拉斯姆斯大学医疗中心 Methods for controlling vasculogenesis

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5183809A (en) * 1990-02-15 1993-02-02 The Trustees Of The University Of Pennsylvania/Childrens Hospital Corporation Cyclodextrin polymers and cyclodextrins immobilized on a solid surface
US5658894A (en) * 1989-04-23 1997-08-19 The Trustees Of The University Of Pennsylvania Compositions for inhibiting restenosis
US5637575A (en) * 1988-01-19 1997-06-10 The Trustees Of The University Of Pennsylvania Methods of inhibiting restenosis
US5760015A (en) * 1988-01-19 1998-06-02 The Trustees Of The University Of Pennsylvania Cyclodextrin compounds and methods of making and use thereof
CA2008534A1 (en) * 1989-01-26 1990-07-26 Donald E. Ingber Method for inhibiting tumor recurrence after surgical resection
US5173481A (en) * 1989-04-03 1992-12-22 The United States Of America As Represented By The Department Of Health And Human Services Preparation of specifically substituted cyclodextrins
US5441944A (en) * 1989-04-23 1995-08-15 The Trustees Of The University Of Pennsylvania Substituted cyclodextrin sulfates and their uses as growth modulating agents
WO1991013100A1 (en) * 1990-03-02 1991-09-05 Australian Commercial Research & Development Limited Cyclodextrin compositions and methods for pharmaceutical and industrial applications
US5227372A (en) * 1990-03-07 1993-07-13 Children's Medical Center Corporation Method for retaining ophthalmological agents in ocular tissues
TW282399B (en) * 1990-05-25 1996-08-01 Takeda Pharm Industry Co Ltd
US5446030A (en) * 1991-09-19 1995-08-29 Weisz; Paul B. Prevention of hemolysis
CA2159717A1 (en) * 1993-03-31 1994-10-13 Elliot Barnathan Methods of affecting the growth of living tissue in mammals and compounds and compositions therefor
EP0706376B2 (en) * 1993-07-19 2007-08-08 Angiotech Pharmaceuticals, Inc. Anti-angiogenic compositions and methods of use
US5753230A (en) 1994-03-18 1998-05-19 The Scripps Research Institute Methods and compositions useful for inhibition of angiogenesis
US7053041B1 (en) 1996-05-31 2006-05-30 The Scripps Research Institute Methods and compositions useful for inhibition of αvβ5mediated angiogenesis
RU2195312C2 (en) 1996-05-31 2002-12-27 Дзе Скриппс Рисерч Инститьют TECHNIQUES AND COMPOSITIONS USED TO INHIBIT αvβ5-CAUSED ANGIOGENESIS
GB9625193D0 (en) * 1996-12-04 1997-01-22 Ml Lab Plc Treatment of highly vascular tumours
AU2006249816A1 (en) * 2005-05-25 2006-11-30 Sirtris Pharmaceuticals, Inc. Treatment of eye disorders with sirtuin modulators
KR20110067130A (en) * 2008-09-22 2011-06-21 아카리오스 비.브이. Carboxyethylated cyclodextrin polysulfates useful as medicaments

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5036422A (en) * 1973-08-07 1975-04-05
US4020160A (en) * 1975-08-15 1977-04-26 American Cyanamid Company Cyclodextrin sulfate salts as complement inhibitors
US4066829A (en) * 1976-07-12 1978-01-03 American Cyanamid Company Malto-dextrin poly(H-)sulfates
JPS53109953A (en) * 1977-11-21 1978-09-26 Osamu Asano Pharmaceutical composition having solid tumor controlling action
US4247535A (en) * 1979-11-05 1981-01-27 American Cyanamid Company Modified cyclodextrin sulfate salts as complement inhibitors
US4258180A (en) * 1979-11-05 1981-03-24 American Cyanamid Company C6-Modified cyclodextrin sulfate salts as complement inhibitors
HU181703B (en) * 1980-05-09 1983-11-28 Chinoin Gyogyszer Es Vegyeszet Process for producing aqueus solutuins of water insoluble or hardly soluble vitamines, steroides, localanesthetics, prostanoides and non-steroid and antiphlogistic agents
US4383992A (en) * 1982-02-08 1983-05-17 Lipari John M Water-soluble steroid compounds
DE3346123A1 (en) * 1983-12-21 1985-06-27 Janssen Pharmaceutica, N.V., Beerse PHARMACEUTICAL PREPARATIONS OF SUBSTANCES MEDICAL OR UNSTABLE IN WATER AND METHOD FOR THE PRODUCTION THEREOF
US4757056A (en) * 1984-03-05 1988-07-12 Hepar Industries, Inc. Method for tumor regression in rats, mice and hamsters using hexuronyl hexosaminoglycan-containing compositions
US4727064A (en) * 1984-04-25 1988-02-23 The United States Of America As Represented By The Department Of Health And Human Services Pharmaceutical preparations containing cyclodextrin derivatives
US4596795A (en) * 1984-04-25 1986-06-24 The United States Of America As Represented By The Secretary, Dept. Of Health & Human Services Administration of sex hormones in the form of hydrophilic cyclodextrin derivatives
JPS61165322A (en) * 1985-01-14 1986-07-26 Microbial Chem Res Found Spergualin composition for pharmaceutical use
GB8506792D0 (en) * 1985-03-15 1985-04-17 Janssen Pharmaceutica Nv Derivatives of y-cyclodextrin
US4783446A (en) * 1985-11-22 1988-11-08 Neushul Mariculture Incorporated Method for the treatment of AIDS virus and other retroviruses
ATE160872T1 (en) * 1990-01-31 1997-12-15 Ladislav Novotny METHOD FOR PRODUCING A CAPILLARY GLASS TUBE FOR MINIATURIZED SENSORS

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101946008A (en) * 2007-12-12 2011-01-12 鹿特丹伊拉斯姆斯大学医疗中心 Methods for controlling vasculogenesis

Also Published As

Publication number Publication date
IE890125L (en) 1989-07-19
DE68910113D1 (en) 1993-11-25
EP0398925A4 (en) 1991-07-03
IE64346B1 (en) 1995-07-26
EP0398925A1 (en) 1990-11-28
GR1000597B (en) 1992-08-26
DK171390D0 (en) 1990-07-17
WO1989006536A1 (en) 1989-07-27
ES2017808A6 (en) 1991-03-01
DK171390A (en) 1990-08-21
JP2995069B2 (en) 1999-12-27
CN1038304C (en) 1998-05-13
EP0398925B1 (en) 1993-10-20
DE68910113T2 (en) 1994-03-17
KR900700114A (en) 1990-08-11
IL88970A (en) 1993-05-13
JPH03502323A (en) 1991-05-30

Similar Documents

Publication Publication Date Title
CN1038304C (en) Growth inhibiting agent and use thereof
CN1083455C (en) Photocurable glycosaminoglycan derivatives, crosslinked glycosaminoglycans and method of production thereof
US5019562A (en) Growth inhibiting agent and the use thereof
CN1303443A (en) Compounds having glucuronic acid derivatives and glucosamine derivatives in structure, process for producing same and utilization thereof
CN101052684A (en) Hydroxyphenyl cross-linked macromolecular network and applications thereof
CN1335749A (en) Method and compositions for treatment of cell proliferative disorders
CN104619352A (en) Compositions containing hc-ha/ptx3 complexes and methods of use thereof
CN1880343A (en) Chemically modified polyaminosaccharide by a hydrocarbyl sultone compound
CN1646171A (en) Novel biomaterials, their preparation and use
JP2005508856A (en) Methods for inhibiting angiogenesis
JP2021516271A (en) Anti-fibrotic compounds, devices, and their use
CN101057859A (en) Depolymerization glycosaminoglycan extracted from sea cucumber composition and its preparation method and application
CN1072654C (en) Benzamide derivative, compsn. containing said derivative and use thereof
CN113995766B (en) Application of digoxin in preparation of medicine for treating and/or preventing osteoarthritis
CN1123005A (en) Compositions, for inhibition, control and regression of angiogenesis, containing hyaluronic acid and nsaid
CN1117498A (en) Prepn. method and application of sodium hyaluronate
CN1642560A (en) Hyaluronic acid mediated adenoviral transduction
CN1113652C (en) Quinazolinone-containing pharmaceutical compositions for prevention of neovascularization and treating human malignancies
JP2004018390A (en) Granulocyte-macrophage colony-stimulating factor secretagogue
CN1084061A (en) Agent for treating cataract and preparation method thereof
JP4463510B2 (en) Glia scar formation inhibitor
CA1306697C (en) Anti-aids virus agent comprising a streptovaricin c derivative
DE3236298C2 (en)
AU626538B2 (en) Growth inhibiting agent and the use thereof
CN116999397A (en) Preparation method and application of double-membrane fusion targeting nano drug delivery system

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C19 Lapse of patent right due to non-payment of the annual fee
CF01 Termination of patent right due to non-payment of annual fee